Sysmex Corporation (HQ: Kobe, Japan; Chairman and CEO: Hisashi Ietsugu) has developed a reagent for testing the degree of hepatic fibrosis during blood testing, using a glycosylation marker1 developed in cooperation with the Research Center for Medical Glycoscience (Director: Hisashi Narimatsu) of the National Institute of Advanced Industrial Science and Technology, or AIST (Tsukuba HQ: Tsukuba, Ibaraki Prefecture, Japan; President: Ryoji Chubachi), building on the successes of New Energy and Industrial Technology Development Organization, or NEDO (HQ: Kawasaki, Kanagawa Prefecture, Japan; Chairman: Kazuo Furukawa) projects*. This reagent received manufacturing and marketing approval on December 10, 2013.
This technology enables clinical laboratories at medical and other institutions to use blood tests to determine the progression of hepatic fibrosis originating from viral hepatitis by determining the progression from chronic hepatitis to cirrhosis of the liver and on to liver cell carcinoma. It also allows this measurement to be made more quickly than was possible with conventional technologies.
This amounts to the world's first practical application of technology employing a glycosylation marker to test hepatic fibrosis.
- *NEDO projects: The Medical Glycomics Project (fiscal 2006 through fiscal 2010), which contributed to the success of realizing the current reagent, employed basic technologies developed through the Glycogene Project (fiscal 2001 through fiscal 2003) and the Structural Glycomics Project (fiscal 2003 through fiscal 2005).
Viral hepatitis is the most prevalent infectious disease in Japan, affecting some 3 million people. Left untreated, the condition can develop into severe illness as it progresses toward liver cell carcinoma. According to Cancer Statistics in Japan produced by the National Cancer Center, as many as 31,800 Japanese people died from liver cell carcinoma in 2011, and liver cancer ranked as the fourth most prevalent type of cancer, following lung cancer, stomach cancer and colon cancer.
As chronic hepatitis advances toward liver cell carcinoma, the amount of fiber-rich tissue in the liver increases and hepatic function gradually declines. Determining the degree of hepatic fibrosis resulting from persistent infection by the hepatitis virus is an important part of the treatment process for viral chronic hepatitis. The typical testing process involves taking a biopsy of the liver tissue (living tissue diagnosis), requiring a patient to be hospitalized. This places a substantial burden on the patient on both the physical and economic fronts. To resolve this issue, the Ministry of Health, Labour and Welfare's "Seven-year Strategy for Hepatitis Research2 calls for the "development of testing methods that allow for the non- invasive evaluation of the degree of fibrosis advancement."
Against this backdrop, NEDO and AIST participated the Medical Glycomics Project (implementation period: fiscal 2006 through fiscal 2010), launched in 2006, to look at structural changes in the sugar chain occurring at the molecular level due to the advancement of hepatic fibrosis, using these as indicators to promote the development of glycosylation markers to enable highly precise diagnosis that was not possible with conventional protein-based biomarkers. The glycosylation marker succeeded in reaching the desired level of accuracy, but measurement was time-consuming, making the technique difficult to deploy in a clinical setting. In 2009, Sysmex joined the NEDO project as a joint developer with the aim of the practical realization of a diagnostic system, working with AIST on technical research and development toward the rapid measurement of glycosylation markers. After the NEDO project concluded in February 2011, Sysmex continued its collaborative research with AIST, working assiduously toward commercialization. To verify the efficacy of this testing method, Sysmex also conducted collaborative research with a number of medical institutions, including the Research Center for Hepatitis and Immunology at the National Center for Global Health and Medicine and the Virology Team at the Nagoya City University Graduate School of Medical Sciences.
2. Result of the development
The glycosylation marker produced through this joint development was used in a reagent to test hepatic fibrosis by determining changes in the sugar chain structure via the Mac-2 binding protein modified isomer3 (M2BPGi), employing a lectin4 that correlates closely to the progression of hepatic fibrosis. A chemiluminescent enzyme-linked immune reaction was used to determine M2BPGi volume through the testing technique of measuring emission intensity, allowing a numeric value to be placed on the degree of advancement of hepatic fibrosis. This testing technique made it possible to determine qualitative changes (changes in the sugar chain structure) on the M2BPGi surface resulting from the fibrosis clinical state, which could not be determined by the protein-based testing methods used in the past, making the testing method substantially more useful5.
At the basic research stage, approximately 18 hours were required for measurement, but our joint development succeeded in reducing this figure to around only 17 minutes, making it a diagnostic system deployable in medical institutions' clinical laboratories. Bringing this testing technology into practical use allows the degree of fibrosis advancement to be measured quickly by means of a blood test rather than requiring hospitalization. This development is expected to substantially reduce the burden on patients being treated for viral chronic hepatitis. This amounts to the world's first practical application of technology employing a glycosylation marker to test hepatic fibrosis.
||Sugar chain, glycosylation marker: Sugar chains, the linked monosaccharides that link to the surface of a cell or a protein, are sometimes described as "cell and protein costumes." Their roles include the transmission of information specific to individual cells and intercellular communications. A glycosylation marker is a biomarker that targets structural changes in sugar changes present in glycoproteins.
||Seven-year Strategy for Hepatitis Research: A national strategy summarized in 2008 by Japan's Ministry of Health, Labour and Welfare. This strategy aims to improve the results of hepatitis treatment by augmenting and reinforcing research on hepatic diseases such as hepatitis, cirrhosis of the liver and liver cancer.
||Mac-2 binding protein sugar chain modified isomer: A sugar chain modified isomer refers to the different sugar chain structure that forms on a protein as cell conditions change, even while the protein portion remains intact. As the sugar chain structure on the Mac-2 binding protein (M2BP) changes in line with the degree to which hepatic fibrosis advances, the detection of both the protein portion and the sugar chain structure can be used as a diagnostic marker. (M2BPGi: Mac-2 binding protein glycosylation isomer)
Lectin: A collective term for carbohydrate-binding proteins. Some 40-50 lectin varieties are known, and these wide-ranging lectins have specific sugar chain structures. Recognizing and combining these sugar chain structures allow the targeting of specific lectins, thereby determining structural changes in the sugar chain.
Basic date from Scientific Reports (Nature Publishing Group), Volume 3, 1065 (2013)
Kuno A, Ikehara Y, Tanaka Y, Ito K, Matsuda A, Sekiya S, Hige S, Sakamoto M, Kage M, Mizokami M, Narimatsu H. A serum "sweet-doughnut" protein facilitates fibrosis evaluation and therapy assessment in patients with viral hepatitis. Sci. Rep. 3, 1065 (2013).
- Information contained in the press release is current as of the date of the announcement,
but may be subject to change without prior notice.